Dataset Information

P38γ and p38δ modulate innate immune response by regulating MEF2D activation

ABSTRACT: Evidence implicating p38γ and p38δ (p38γ/p38δ) in inflammation are mainly based on experiments using p38γ/p38δ deficient (p38γ/δ-/-) mice, which show low levels of TPL2, the kinase upstream of MKK1-ERK1/2 in myeloid cells. This could obscure p38γ/p38δ roles, since TPL2 is essential for regulating inflammation. Here we generated a p38γD171A/D171A/p38δ-/- (p38γ/δKIKO) mouse, expressing kinase-inactive p38γ and lacking p38δ. This mouse exhibited normal TPL2 levels, making it an excellent tool to elucidate specific p38γ/p38δ functions. p38γ/δKIKO mice showed a reduced inflammatory response and less susceptibility to LPS-induced septic shock and Candida albicans infection than wild-type mice. Gene expression analyses in LPS-activated WT and p38γ/δKIKO macrophages revealed that p38γ/p38δ regulated numerous genes implicated in innate immune response. Additionally, phospho-proteomic analyses and in vitro kinase assays showed that the transcription factor myocyte enhancer factor-2D (MEF2D) was phosphorylated at Ser444 via p38γ/p38δ. Mutation of MEF2D Ser444 to the non-phosphorylatable residue Ala increased its transcriptional activity and the expression of iNOS and IL-1β mRNA. These results suggest that p38γ/p38δ govern innate immune responses by regulating MEF2D phosphorylation and transcriptional activity.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Cell Culture

SUBMITTER: Eric Bonneil

LAB HEAD: Ana Cuenda

PROVIDER: PXD042626 | Pride | 2023-08-10

REPOSITORIES: Pride

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			Action	DRS
	Service_Sonenberg_150119_1.mgf	Mgf
	Service_Sonenberg_150119_1.raw	Raw
	Service_Sonenberg_150119_10.mgf	Mgf
	Service_Sonenberg_150119_10.raw	Raw
	Service_Sonenberg_150119_11.mgf	Mgf

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p38γ and p38δ modulate innate immune response by regulating MEF2D activation.

Escós Alejandra A Diaz-Mora Ester E Pattison Michael M Fajardo Pilar P González-Romero Diego D Risco Ana A Martín-Gómez José J Bonneil Éric É Sonenberg Nahum N Jafarnejad Seyed Mehdi SM Sanz-Ezquerro Juan José JJ Ley Steven C SC Cuenda Ana A

eLife 20230717

Evidence implicating p38γ and p38δ (p38γ/p38δ) in inflammation are mainly based on experiments using Mapk12/Mapk13-deficient (p38γ/δKO) mice, which show low levels of TPL2, the kinase upstream of MKK1-ERK1/2 in myeloid cells. This could obscure p38γ/p38δ roles, since TPL2 is essential for regulating inflammation. Here, we generated a Mapk12D171A/D171A/Mapk13-/- (p38γ/δKIKO) mouse, expressing kinase-inactive p38γ and lacking p38δ. This mouse exhibited no ...[more]

PMID: 37458356

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